Azole derivatives, process for their preparation and their use

ABSTRACT

Azole derivatives, process for their preparation, and their use 
     Azole derivatives of the formula (I) ##STR1## in which A, L, O, R 1 , X, Y, Z and q have the meanings given, process for their preparation, pharmaceutical preparations and the use of the compounds are described. Azole derivatives of the formula I where the symbols have for example the following meanings: 
     R 1  is (C 2  -C 10 )-alkyl, 
     Z is nitrogen, 
     X and Y are independently of one another CR 2 , 
     L is --CH 2  --, 
     q is zero or 1, 
     A is a biphenyl radical which is substituted for example by R 15 , 
     R 2  is halogen or hydrogen, 
     R 15  is SO 2  --NH--CO--OR 6  and 
     R 6  is phenyl, 
     are highly active antagonists of angiotensin II receptors.

This application is a continuation of prior application Ser. No.07/806,634 filed Dec. 13, 1991, now abandoned.

Growing importance is attached to the development of novel angiotensinII receptor antagonists. 1-Benzyl-substituted imidazole derivatives areknown from EP-A-28,834, imidazole derivatives having a diarylcarboxylicfunction are known from EP-A-253,310 and EP-A-0,401,030, pyrazole andtriazole derivatives are known from EP-A-323,841 and triazolederivatives in each case having a diarylcarboxylic function are knownfrom EP-A-0,409,332, and imidazole derivatives having a diaryltetrazolylgroup and their use as antagonists of angiotensin II receptors are knownfrom EP-A-324,377.

Moreover, substituted azoles which contain a sulfonylurea group arepresented in DE-A-4,010,797 (corresponding to U.S. patent applicationNo. 07/679.233).

Novel azole derivatives have been found which have a novel sulfonylurea,sulfonylurethane or a sulfonylsulfonamide structure and which are highlyactive antagonists of angiotensin II receptors both in vitro and invivo.

The invention relates to compounds of the formula I ##STR2## in whichthe symbols have the following meanings:

a) X, Y and Z are identical or different and are N or CR²,

b) R¹ is

1. (C₂ -C₁₀)-alkyl,

2. (C₃ -C₁₀)-alkenyl,

3. (C₃ -C₁₀)-alkynyl,

4. --OR³,

5. (C₃ -C₈)-cycloalkyl,

6. (C₄ -C₁₀)-cycloalkylalkyl,

7. (C₅ -C₁₀)-cycloalkylalkenyl,

8. (C₅ -C₁₀)-cycloalkylalkynyl,

9. --(CH₂)_(m) --B--(CH₂)_(n) --R⁴,

10. -benzyl,

11. a radical as defined under b) 1., 2., 3. or 9 , which ismonosubstituted by CO₂ R³,

12. a radical defined as under b) 1., 2., 3. or 9., in which 1 to all ofthe hydrogen atoms are substituted by fluorine, or

13. the radical defined under b) 10., which is substituted on the phenylby 1 or 2 identical or different radicals from the series comprisinghalogen, (C₁ -C₄)-alkoxy and nitro;

c) R² is

1. hydrogen,

2. halogen,

3. nitro,

4. C_(v) F_(2v+1),

5. pentafluorophenyl,

6. cyano,

7. --O--R⁶,

8. phenyl,

9. phenyl-(C₁ -C₃)-alkyl,

10. (C₁ -C₁₀)-alkyl,

11. (C₃ -C₁₀)-alkenyl,

12. phenyl-(C₂ -C₆)-alkenyl,

13. 1-imidazolyl-(CH₂)_(m) --,

14. 1,2,3-triazolyl-(CH₂)_(n) --,

15. tetrazolyl-(CH₂)_(m) --,

16. --(CH₂)_(o-1) --CHR⁷ --OR⁵,

17. --(CH₂)_(o) --O--CO--R³,

18. --(CH₂)_(o) --S--R⁶,

19. --S(O)_(r) --R¹⁹,

20. --CH═CH--(CH₂)_(m) --CHR³ --OR⁶,

21. --CH₂ ═CH--(CH₂)_(m) --CO--R⁸,

22. --CO--R⁸,

23. --CH═CH--(CH₂)_(m) --O--CO--R⁷,

24. --(CH₂)_(m) --CH(CH₃)--CO--R⁸,

25. --(CH₂)_(o) --CO--R⁸, ##STR3## 28. --(CH₂)_(o) --NR⁷ --CO--NHR⁹, 29.--(CH₂)_(o) --NR⁷ --SO₂ R⁹, ##STR4## 31. --(CH₂)_(n) F, 32. --(CH₂)_(n)--O--NO₂,

33. --(CH₂ --N₃,

34. --(CH₂)_(n) --NO₂,

35. --CH═N--NR⁵ R⁷,

36. phthalaimido-(CH₂)_(n) --, ##STR5## 43. --(CH₂)_(n) --SO₂ --NR⁷--CS--NR⁶ R⁹,

44. --(CH₂)_(n) --SO₂ --NR⁷ --CO--NR⁶ R⁹,

45. --(CH₂)_(o) --SO₂ R⁹,

46. a radical defined as under c) 8. or 9., which is substituted on thephenyl by 1 or 2 identical or different radicals from the seriescomprising halogen, hydroxyl, methoxy, trifluoromethyl, CO₂ R³ andphenyl,

47. a radical defined as under c) 10., 11. or 19., in which one to allof the hydrogen atoms are substituted by fluorine, or

48. the radical defined under c) 14., which is substituted by 1 or 2identical or different radicals from the series comprisingmethoxycarbonyl and (C₁ -C₄ )-alkyl,

49. --(CH₂)_(n) --SO₂ --NR⁷ --CO--R⁶,

50. --(CH₂)_(n) --SO₂ --NR⁷ --CS--R⁶ ;

d) R.sup. 3 is

1. hydrogen,

2. (C₁ --C₈)-alkyl,

3. (C₃ -C₈)-cycloalkyl,

4. phenyl,

5. benzyl or

6. the radical defined under d) 2., in which 1 to all of the hydrogenatoms are substituted by fluorine;

e) R⁴ is

1. hydrogen,

2. (C₁ -C₆)-alkyl,

3. (C₃ -C₈)-cycloalkyl,

4. (C₂ -C₄)-alkenyl or

5. (C₂ -C₄)-alkynyl;

f) R⁵ is

1. hydrogen,

2. (C₁ -C₆)-alkyl,

3. (C₃ -C₈)-cycloalkyl,

4. phenyl or

5. benzyl;

g) R⁶ and R⁹ are identical or different and are

1. hydrogen

2. (C₁ -C₆)-alkyl which can be substituted by 1-3 radicals from theseries comprising (C₁ -C₆)-alkoxy, which for its part can be substitutedby 1-3 radicals from the series comprising hydroxyl, (C₁ -C₆)-alkoxy,amino, mono-(C₁ -C₆)-alkylamino and di-(C₁ -C₆)-alkylamino, or can besubstituted by (C₂ -C₁₀)-alkenyl, hydroxyl, amino, mono-(C₁-C₆)-alkylamino, di-(C₁ -C₆)-alkylamino, (C₁ -C₆)-alkoxycarbonylamino,(C₆ -C₁₂)-aryl-(C₁ -C₄)-alkoxycarbonylamino, (C₆ -C₁₀)-aryl, (C₆-C₁₀)-aryl(C.sub. -C₃)-alkyl, (C₁ -C₉)-heteroaryl, carboxyl and (C₁-C₄)-alkoxycarbonyl,

3. (C₃ -C₈)-cycloalkyl, where the cycloalkyl moiety can additionally besubstituted by 1-3 radicals from the series comprising (C₁ -C₄)-alkyland (C₂ -C₄)-alkenyl,

4. (C₃ -C₈)-cycloalkyl-(C₁ -C₃)-alkyl,

5. (C₆ -C₁₂)-aryl, preferably phenyl,

6. (C₆ -C₁₀)-aryl-(C₁ -C₄)-alkyl,

7. (C₁ -C₉)-heteroaryl which can be partially or completelyhydrogenated,

8. a radical defined as under g) 5., 6., 7., 9., 15., 16., 17., 19., 20.or 21., substituted by 1 or 2 identical or different radicals from theseries comprising halogen, hydroxyl, (C₁ -C₄)-alkyl, methoxy, nitro,cyano, CO₂ R³, trifluoromethyl, --NR¹¹ R¹² and ##STR6## 9. (C₁-C₉)-heteroaryl-(C₁ -C₃)-alkyl, where the heteroaryl moiety can bepartially or completely hydrogenated,

10. (C₁ -C₆)-alkyl in which 1 to all hydrogen atoms are substituted byfluorine,

11. (C₂ -C₁₀)-alkenyl, (C₂ -C₁₀)-alkenoyl or (C₂ -C₁₀)-alkadienyl,

12. (C₃ -C₈)-cycloalkenyl,

13. (C₃ -C₈)-cycloalkenyl-(C₁ -C₃)-alkyl,

14. bi- or tricyclic (C₄ -C₁₀)-cycloalkenyl-(C₁ -C₄)-alkyl which canadditionally be substituted by 1-3 (C₁ -C₄)-alkyl radicals,

15. (C₆ -C₁₀)-aryl-(C₁ -C₄)-alkyl,

16. (C₆ -C₁₀)-aryl-(C₃ -C₆)-alkenyl,

17. (C₁ -C₉)-hetaryl-(C₃ -C₆)-alkenyl,

18. (C₃ -C₆)-alkynyl,

19. (C₆ -C₁₀)-aryl-(C₃ -C₆)-alkynyl,

20. (C₁ -C₉)-hetaryl-(C₃ -C₆)-alkynyl,

21. R⁶ and R⁹, together with the N atom carrying them, are a hetaryl,which can also be partially or completely hydrogenated;

h) R⁷ is

1. hydrogen,

2. (C₁ -C₆)-alkyl,

3. (C₃ -C₈)-cycloalkyl,

4. (C₆ -C₁₂)-aryl-(C₁ -C₆)-alkyl, preferably benzyl,

5. phenyl or

6. (C₁ -C₉)-heteroaryl;

i) R⁸ is

1. hydrogen,

2. (C₁ -C₆)-alkyl,

3. (C₃ -C₈)-cycloalkyl,

4. phenyl-(CH₂)_(q) --,

5. OR⁶,

6. NR¹¹ R¹² or ##STR7##

j) R¹⁰ is cyano, nitro or CO₂ R⁷ ;

k) R¹¹ and R¹² are identical or different and are

1. hydrogen,

2. (C₁ -C₄)-alkyl,

3. phenyl,

4. benzyl or

5. α-methylbenzyl;

l) D is NR¹³, O or CH₂ ;

m) R¹³ is hydrogen, (C₁ -C₄)-alkyl or phenyl;

n) A is a biphenyl radical which can be substituted by up to 4,preferably up to 2, identical or different radicals R¹⁴ or R¹⁵, where A,however, is compulsorily substituted by at least one radical definedunder p) 44. or 45.

o) R¹⁴ is

1. halogen,

2. nitroso,

3. nitro,

4. amino,

5. cyano,

6. hydroxyl,

7. (C₁ -C₆)-alkyl,

8. (C₁ -C₄)-alkanoyl,

9. (C₁ -C₄)-alkanoyloxy,

10. CO₂ R³,

11. methanesulfonylamino,

12. trifluoromethanesulfonylamino,

13. --CO--NH--OR⁹,

14. --SO₂ --NR⁶ R⁷,

15. --CH₂ --OR⁷,

16. (C₁ -C₉)-heteroaryl-(CH₂)_(q) --, preferably 1-tetrazolyl,

17. (C₇ -C₁₃)-aroyl, ##STR8## 20. (C₆ -C₁₂)-aryl;

p) R¹⁵ is

1. hydrogen,

2. (C₁ -C₆)-alkyl,

3. (C₃ -C₈)-cycloalkyl,

4. (C₈ -C₁₂)-aryl,

5. (C₇ -C₁₃)-aroyl,

6. (C₁ -C₄)-alkoxy,

7. (C₁ -C₄)-alkanoyloxy,

8. (C₁ -C₉)-heteroaryl,

9. CO₂ R³,

10. halogen,

11. cyano,

12. nitro,

13. NR⁶ R⁷,

14. hydroxyl,

15. --CO--NH--CHR⁵ --CO₂ R³,

16. sulfo,

17. --SO₃ R³,

18. --SO₂ --NR⁷ --CO--NR⁶ R⁹ or --SO₂ --NR⁷ --CS--NR⁶ R⁹,

19. --NR⁷ --CO--NR⁷ SO₂ --CH₂ --R⁵,

20. --C (CF₃)₂ OH,

21. phosphonooxy,

22. --PO₃ H₂,

23. --NH--PO(OH)₂,

24. --S(O)^(r) R⁶,

25. --CO--R⁸,

26. --CO--NR⁶ R⁹,

27. --CR²⁰ (OH)--PO(OH)₂,

28. the radical defined under o) 20. ##STR9## 32.5-tetrazolyl--NH--CO--, 33. --CO--NH--NH--SO₂ CF₃, ##STR10## 40.--CO--NH--SO₂ --R¹⁹, 41. --SO₂ --NH--CO--R⁶ or

42. the radical defined under p) 4., substituted by 1 or 2 identical ordifferent radicals from the series comprising halogen, cyano, nitro,NR6R⁷ and hydroxyl;

43. R¹⁵ together with R¹⁴ is --CO--NH--SO₂ --,

44. --SO₂ --NH--CO--O--R⁶

45. --SO₂ --NH--SO₂ --NR⁶ R⁹

46. --SO₂ --NH--SO₂ --R⁶

q) B is O, NR⁷ or S;

r) W is O or S;

s) L is (C₁ -C₃)-alkanediyl;

t) R¹⁶ is CO₂ R³ or CH₂ CO₂ R³ ;

u) R¹⁷ is hydrogen, halogen, (C₁ -C₄)-alkyl or (C₁ -C₄)-alkoxy;

v) R¹⁸ is hydrogen, (C₁ -C₄)-alkyl or phenyl;

w) R¹⁹ is

1. (C₁ -C₆)-alkyl,

2. (C₃ -C₈)-cycloalkyl,

3. phenyl,

4. benzyl or

5. the radical defined under w) 1., in which one to all of the hydrogenatoms are substituted by fluorine;

x) T is

1. a single bond,

2. --CO--,

3. --CH₂ --,

4. --O--,

5. --S--,

6. --NR²¹ --,

7. --CO--NR²¹ --,

8. --NR²¹ --CO--,

9. --O--CH₂ --,

10. --CH₂ --O--,

11. --S--CH₂ --,

12. --CH₂ --S--,

13. --NH--CR₂₀ R²² --,

14. --NR²¹ --SO₂ --,

15. SO₂ --NR²¹ --,

16. --CR₂₀ R²² --NH--,

17. --CH═CH--,

18. --CF═CF--,

19. --CH═CF--,

20. --CF═CH--,

21. --CH₂ --CH₂ --,

22. --CF₂ --CF₂ --,

23. --CH(OR³)--

24. --CH(OCOR⁵)-- ##STR11##

y) R²⁰ and R²² are identical or different and are hydrogen, (C₁-C₅)-alkyl, phenyl, allyl or benzyl;

z) R²¹ is hydrogen, (C₁ -C₆)-alkyl, benzyl or allyl;

a') R²³ is

1. NR²⁰ R²¹,

2. ureido,

3. thioureido,

4. toluene-4-sulfonyl or

5. benzenesulfonylamino;

b') R²⁴ and R²⁵ are identical or different and are (C₁ -C₄)-alkyl ortogether are --(CH₂)_(q) --;

c') Q is CH₂, NH, O or S;

d') m is an integer from O to 5;

e') n is an integer from 1 to 5;

f') o is an integer from 1 to 10;

g') q is 0 or 1;

h') r is 0, 1 or 2, or

i') v is an integer from 1 to 6;

and their physiologically tolerable salts with the exception of thecompound of the formula α ##STR12##

Alkyl, alkenyl and alkynyl can be straight-chain or branched. The sameapplies to radicals derived therefrom, such as alkanoyl or alkoxy.

Cycloalkyl is also understood as meaning alkyl-substituted rings.

(C₆ -C₁₂)-aryl is, for example, phenyl, naphthyl or biphenylyl,preferably phenyl. The same applies to radicals derived therefrom, suchas aroyl or aralkyl.

(C₁ -C₉)-heteroaryl is in particular understood as meaning radicalswhich are derived from phenyl or naphthyl, in which one or more CHgroups are replaced by nitrogen and/or in which at least two adjacent CHgroups are replaced (with the formation of a five-membered aromaticring) by S, NH or O. In addition, one or two atoms of the condensationsite of bicyclic radicals (such as in indolizinyl) can also be nitrogenatoms.

Heteroaryl is in particular also furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl,indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl,quinazolinyl and cinnolinyl.

Stereocenters which may occur can be of both (R) and (S) configuration.

The linkage of A takes place via an alkanediyl bridge L which ispreferably a methylene group.

The methylene group is preferably directly bonded to the biphenylradical.

Physiologically tolerable salts of compounds of the formula (I) areunderstood as meaning both their organic and their inorganic salts, suchas are described in Remington's Pharmaceutical Sciences (17th edition,page 1418 (1985)). Owing to the physical and chemical stability and thesolubility, sodium, potassium, calcium and ammonium salts, inter alia,are preferred for acid groups; salts of hydrochloric acid, sulfuricacid, phosphoric acid or of carboxylic acids or sulfonic acids, such as,for example, acetic acid, citric acid, benzoic acid, maleic acid,fumaric acid, tartaric acid and p-toluenesulfonic acid, inter alia, arepreferred for basic groups.

Preferred compounds of the formula I are those in which

a) X is N, Y is CR² and Z is CR² ;

b) X is CR², Y is N and Z is CR² ;

c) X is CR², Y is CR² and Z is N

or

d) X, Y and Z are in each case N.

Compounds of the formula (I) are additionally preferred in which thesymbols have the following meanings:

X is N, Y is CR₂ and Z is CR² ;

X is CR², Y is N and Z is CR² ;

X is CR², Y is CR² and Z is N,

or

X, Y and Z are in each case N,

a) R¹ is

1. (C₂ -C₁₀)-alkyl,

2. (C₃ -C₁₀)-alkenyl,

3. (C₃ -C₁₀)-alkynyl,

4. (C₃ -C₈)-cycloalkyl,

5. benzyl or

6. benzyl which is substituted as described above (b 13.);

b) R² is

1. hydrogen,

2. halogen,

3. nitro,

4. C_(v) F_(2v+1),

5. pentafluorophenyl,

6. cyano,

7. --O--R⁶,

8. phenyl,

9. phenyl-(C₁ -C₃)-alkyl,

10. (C₁ -C₁₀)-alkyl,

11. (C₃ -C₁₀)-alkenyl,

12. phenyl-(C₂ -C₆)-alkenyl,

13. 1-imidazolyl-(CH₂)_(m) --,

14. 1,2,3-triazolyl-(CH₂)_(o) --,

15. tetrazolyl-(CH₂)_(m) --,

16. --(CH₂)_(o-1) --CHR⁷ --OR⁵,

17. --(CH₂)_(o) --O--COR³,

18. --COR⁸,

19. --(CH₂)_(o) --CO--R⁸,

20. S(O)_(r) R¹⁹,

21. --CH═CH--(CH₂)_(m) --CHR³ --OR⁶,

22. --CH₂ ═CH--(CH₂ )_(m) --CO--R⁸,

23. --(CH₂)_(o) --NH--CO--OR⁹,

24. --(CH₂)_(o) --NH--SO₂ --R⁹,

25. --(CH₂)_(n) F,

26. --(CH₂)_(o) --SO₃ R⁹,

27. --(CH₂)_(n) --SO₂ --NH--CO--NR₆ R⁹,

28. --(CH₂)_(n) --SO₂ --NH--CS--NR⁶ R⁹, or

29. a radical defined as under b) 8., 9., 10., 11. or 14., which issubstituted as above under c) 46., 47. or 48. in each case as describedfor such a radical,

30. --(CH₂)_(n) --SO₂ --NR⁷ --CO--R⁶,

31. --(CH₂)_(n) --SO₂ --NR⁷ --CS--R⁶ ;

c) R⁸ is hydrogen, (C₁ -C.sub.)-alkyl, OR⁶, NR¹¹ R¹² or morpholino;

d) T is

1. a single bond,

2. --CO--,

3. --CONR²¹ --,

4. --CH₂ --CH₂ --,

5. --NR²¹ --CO--,

6. --O--CH₂ --,

7. --CH₂ --o--,

8. --S--CH_(26l) --,

9. --CH₂ --S--,

10. --NH--CH₂ --,

11. --CH₂ --NH-- or

12. --CH═CH--

and the other radicals and variables are as defined above.

Particularly preferred compounds of the formula (I) are those in which

X is N, Y is CR² and Z is CR² ;

X is CR², Y is N and Z is CR² ;

X is CR², Y is CR² and Z is N

or

X, Y and Z are in each case N,

a) R¹ is (C₂ -C₇)-alkyl, (C₃ -C₇)-alkenyl or (C₃ -C₇)-alkynyl;

b) R² is

1. chlorine,

2. bromine,

3. C_(v) F_(2v+1) where v=1, 2 or 3,

4. pentafluorophenyl,

5. O--R⁶,

6. --S(O)_(r) R¹⁹,

7. (CH₂)_(o-1) --CHR⁷ --OR⁵,

8. (CH₂)_(o) --O--CO--R³,

9. --COR⁸,

10. --(CH₂)_(o) --CO--R⁸,

11. --CH₂ --NH--CO--R⁸,

12. --(CH₂)_(o) --NH--SO₂ --R⁹,

13. --CH═CH--CHR³ --OR⁶,

14. tetrazolyl-(CH₂)_(m) --,

15. --(CH₂)_(n) SO₂ --NH--CO--NR⁶ R⁹,

16. --(CH₂)_(o) --SO₃ R⁹ or (C₁ -C₆)-alkyl which is optionallysubstituted by hydroxyl, preferably hydroxymethyl;

c) R³ is hydrogen, (C₁ -C₄)-alkyl or benzyl;

d) R⁶ and R⁹ are identical or different and are

1. hydrogen

2. (C₁ -C₆)-alkyl which can be substituted by 1-3 radicals from theseries comprising (C₁ -C₆)-alkoxy, which for its part can be substitutedby 1-3 radicals from the series comprising hydroxyl, (C₁ -C₆)-alkoxy,amino, mono-(C₁ -C₆)-alkylamino and di-(C₁ -C₆ -alkylamino, or can besubstituted by (C₂ -C₁₀)-alkenyl, hydroxyl, amino, mono-(C₁-C₆)-alkylamino, di-(C₁ -C₆)-alkylamino, (C₁ -C₆)-alkoxycarbonylamino,(C₆ -C₁₂)-aryl-(C₁ -C₄)-alkoxycarbonylamino, (C₆ -C₁₀)-aryl, (C₆-C₁₀)-aryl (C₁ -C₃)-alkyl, (C₁ -C₉)-heteroaryl, carboxyl and (C₁-C₄)-alkoxycarbonyl;

3. (C₃ -C₆)-cycloalkyl,

4. (C₃ -C₆)-cycloalkyl-(C₁ -C₃)-alkyl,

5. phenyl,

6. phenyl-(C₁ -C₃)-alkyl,

7. (C₁ -C₇)-heteroaryl which can be partially or completelyhydrogenated,

8. a radical defined as under g) 5., 6., 7. or 9., 14.-16. and 18.-20.,substituted by 1 or 2 identical or different radicals from the seriescomprising halogen, hydroxyl, (C₁ -C₄)-alkyl, methoxy, nitro, cyano, CO₂R³, trifluoromethyl, --NR¹¹ R¹² and ##STR13## 9. (C₁ -C₉)-heteroaryl-(C₁-C₃)-alkyl, where the heteroaryl moiety can be partially or completelyhydrogenated,

10. (C₁ -C₆)-alkyl, in which 1 to all hydrogen atoms are substituted byfluorine,

11. (C₂ -C₄)-alkenyl or (C₃)-alkenoyl,

12. (C₃ -C₆)-cycloalkenyl,

13. (C₃ -C₆)-cycloalkenyl-(C₁ -C₃)-alkyl,

14. bi- or tricyclic (C₄ -C₁₀)-cycloalkenyl-(C₁ -C₄)-alkyl which canadditionally be substituted by 1-3 (C₁ -C₄)-alkyl radicals;

15. C₆ -aryl-(C₁ -C₃)-alkyl,

16. C₆ -aryl-(C₃)-alkenyl,

17. (C₁ -C₆)-hetaryl-(C₃)-alkenyl,

18. C₃ -alkynyl,

19. C₃ -aryl-(C₃)-alkynyl,

20. (C₁ -C₆)-hetaryl-(C₃)-alkynyl,

21. R⁶ and R⁹, together with the N atom carrying them, are a hetarylwhich can also be partially or completely hydrogenated;

e) R⁷ is hydrogen, (C₁ -C₄)-alkyl, (C₁ -C₉)-heteroaryl, or (C₆-C₁₂)-aryl-(C₁ -C₄)-alkyl;

f) R⁸ is hydrogen, (C₁ -C₄)-alkyl, OR⁶ or morpholino;

g) R¹⁴ is

1. (C.sub. -C₄)-alkyl,

2. (C₁ -C₄)-alkoxy,

3. cyano,

4. amino,

5. nitroso,

6. nitro,

7. fluorine,

8. chlorine,

9. bromine,

10. (C₁ -C₉)-heteroaryl-CH₂ --,

11. (C₁ -C₄)-alkanoyloxy,

12. (C₁ -C₄)-alkanoyl,

13. benzoyl,

14. --NH--CO--R⁷ or

15. tetrazolyl;

h) R¹⁵ is

1. (C₁ -C₄)-alkyl,

2. (C₆ -C₁₂)-aryl,

3. (C₁ -C₃)-alkanoyloxy,

4. (C₁ -C₄)-alkoxy,

5. (C₁ -C₉)-heteroaryl, preferably 5-tetrazolyl,

6. cyano,

7. nitro,

8. hydroxyl,

9. --S(O)_(r) R⁶,

10. --SO₃ R³,

11. chlorine,

12. bromine,

13. benzoyl,

14. --CO₂ R³,

15. --CO--NH--R⁶,

16. --CO--R⁸,

17. --SO₂ --NR⁶ R⁷,

18. --SO₂ --NH--CO--NR⁶ R⁹,

19. --PO₃ H,

20. --CO--CHR⁵ --CO₂ H,

21. --NH--CO--NH--SO₂ --CH₂ --R⁵,

22. 5-tetrazolyl-NH--CO--, ##STR14## 28. the radical defined under h)2), substituted as defined above (see p) 42),

29. R¹⁵ together with R¹⁴ is --CO--NH--SO₂ --;

30. --SO₂ --NH--COO--R⁶ ;

31. --SO₂ --NH--SO₂ --NR⁶ R⁹ ;

32. --SO₂ --NH--SO₂ --R⁹ ;

i) R¹⁸ is hydrogen, methyl or ethyl;

j) T is a single bond, --O--, --CO--, --NHCO-- or --OCH.sub. --;

k) q=0 and L is methylene

and the other radicals and variables are as defined above.

Particularly preferred azole derivatives are moreover those of thegeneral formula (I) in which Z is a nitrogen atom and Y and X areindependently of one another CR² and the remaining symbols are asdefined above.

Particularly suitable azole derivatives are additionally those of thegeneral formula (I) where the symbols have the following meaning:

Z is nitrogen,

X and Y are independently of one another CR²,

R¹ is (C₂ -C₇)-alkyl, (C₃ -C₇)-alkenyl or (C₃ -C₇)-alkynyl,

R² is hydrogen, halogen, nitro, (C₁ -C₃)-perfluoroalkyl, cyano, C₁-C₁₀)-alkyl, (C₃ -C₁₀)-alkenyl, --CH₂ OR⁵, --S(O)_(r) --R¹⁹, --CO--R⁸ or--O--R⁶,

R⁵ is hydrogen or (C₁ -C₆)-alkyl,

R⁶ and R⁹ are

1. hydrogen,

2. (C₁ -C₆)-alkyl which can be substituted by 1-3 radicals from theseries comprising (C₁ -C₆)-alkoxy, which for its part can be substitutedby 1-3 radicals from the series comprising hydroxy, (C₁ -C₆)-alkoxy,amino, mono-(C₁ -C₆)-alkylamino and di-(C₁ -C₆)-alkylamino, or can besubstituted by (C₂ -C₁₀)-alkenyl, hydroxyl, amino, mono-(C₁-C₆)-alkylamino, di-(C₁ -C₆)-alkylamino, (C₁ -C₆)-alkoxycarbonylamino,(C₁ -C₁₂)-aryl-(C₁ -C₄)-alkoxycarbonylamino, (C₆ -C₁₀)-aryl, (C₆-C₁₀)-aryl-(C₁ -C₃)-alkyl, (C₁ -C₉)-heteroaryl, carboxyl and (C₁-C₄)-alkoxycarbonyl;

3. (C₃ -C₈)-cycloalkyl,

4. (C₃ -C₆)-cycloalkyl-(C₆ -C₃)-alkyl

5. (C₆ -C₁₂)-aryl, preferably phenyl,

6. (C₆ -C₁₀)-aryl-(C₁ -C₄)-alkyl,

7. (C₁ -C₉)-heteroaryl, which can be partially or completelyhydrogenated,

8. (C₁ -C₉)-heteroaryl-(C₁ -C₃)-alkyl, where the heteroaryl moiety canbe partially or completely hydrogenated,

9. a radical defined as above under 5., 6., 7., and 8. substituted by 1or 2 identical or different radicals from the series comprising halogen,hydroxyl, (C₁ -C₄)-alkyl, methoxy, nitro, cyano, CO₂ R³,trifluoromethyl, --NR¹¹ R¹² and ##STR15## 10. (C₁ -C₆)-alkyl, in which 1to all hydrogen atoms are substituted by fluorine,

11. (C₂ -C₆)-alkenyl or (C₃ -C₆)-alkenoyl,

12. (C₃ -C₈)-cycloalkenyl,

13. (C₆ -C₈)-cycloalkenyl-(C₁ -C₃)-alkyl,

14. (C₆ -C₁₀)-aryl-(C₁ -C₄)-alkyl,

15. (C₆ -C₁₀)-aryl-(C₃ -C₆)-alkenyl,

16. (C₁ -C₉)-hetaryl-(C₃ -C₆)-alkenyl,

17. (C₃ -C₆)-alkynyl,

18. (C₆ -C₁₀)-aryl-(C₃ -C₆)-alkynyl,

19. (C₁ -C₉)-hetaryl-(C₃ -C₆)-alkynyl,

20. R⁶ and R⁹, together with the N atom carrying them, are a hetarylwhich can also be partially or completely hydrogenated,

R⁷ is hydrogen,

R⁸ is hydrogen or --OR⁶,

R¹¹ and R¹² are independently of one another hydrogen or (C₁ -C₄)-alkyl,

D is --NR¹³, --O or --CH₂,

R¹³ is hydrogen or (C₁ -C₄)-alkyl,

A is a biphenyl radical which is substituted by a radical R¹⁵ or by R¹⁴and R¹⁵ together,

R¹⁵ is --SO₂ --NR⁷ --CO--NR⁶ R⁹, --SO₂ --NH--COO--R⁶, --SO₂ --NH--SO₂--NR⁶ R⁹, --SO₂ --NH--CO--R⁶ or --SO₂ --NH--SO₂ --R⁶ ; or

R¹⁴ and R¹⁵ together can be --CO--NH--SO₂ --,

L is --CH₂ --,

q is zero and

r is zero, 1 or 2,

and their physiologically tolerable salts.

The invention also relates to a process for the preparation of compoundsof the formula (I), and of their physiologically tolerable salts, whichcomprises alkylating compounds of the formula (II) ##STR16## in whichR¹, X, Y and Z are as defined above, with compounds of the formula (III)

    U--L--(O).sub.q --A                                        (III)

in which L, A and q are as defined above, and U is a leaving group, ifappropriate removing temporarily introduced protective groups andconverting sulfonamides of the formula I obtained, if appropriate, intourethanes of the formula I, converting sulfonamides of the formula Iobtained or urethanes of the formula I obtained, if appropriate, intosulfonylureas of the formula I and converting the compounds of theformula (I) obtained, if appropriate, into their physiologicallytolerable salts.

Suitable leaving groups U are preferably nucleofugic groups (cf. Angew.Chem. 72 [1960] 71) such as halogen, o-toluenesulfonate, mesylate ortriflate.

Processes for the preparation of the precursors of the formula (II) areknown, inter alia, from U.S. Pat. No. 4,355,044, EP-A-324,377 andEP-A-323,841.

Other processes are described by G. L'abbe (Chem. Rev. 69, 345 (1969)),T. Srodsky ("The Chemistry of the Azido Group", Wiley, New York, 1971,p. 331), H. Wamhoff ("Comprehensive Heterocyclic Chemistry") and by S.Katritzky Ed., Pergamon Press, New York (1984)).

Another process for the preparation of compounds of the formula IIstarts from 1-cyanoglyoxylic acid 2-oxime derivatives and afterreduction of the oxime with reductants known from the literature andaddition of mercapto compounds to the nitrile group using suitableprotective groups yields precursors which can be cyclized underdehydrating conditions to give imidazoles. For the cyclization step,inter alia, mixtures of PCl₅ and dimethylaminopyridine (DMAP), POCl₃ andSOCl₂ and their mixtures with DMAP can be used.

The oxidation of the thio compounds of the formula I where R² is--S(O)_(r) R¹⁹ and in which R is zero or 1 to the corresponding sulfonesand sulfoxides is preferably carried out by means of peracids insuitable solvents such as, for example, dichloromethane.

To alkylate the azoles of the formula (II), suitable alkylating agentsare, for example, appropriate benzyl halides, tosylates, mesylates ortriflates or appropriate alkyl halides, tosylates, mesylates ortriflates.

The alkylation is carried out in an analogous manner to processes whichare known in principle.

Azole derivatives of the formula (II) are metalated, for example, in thepresence of a base. Preferred bases are metal hydrides of the formula MHsuch as, for example, lithium hydride, sodium hydride or potassiumhydride in, for example, DMF or DMSO as a solvent or metal alkoxides ofthe formula MOR, where R is methyl, ethyl or t-butyl, and the reactionis carried out in the corresponding alcohol, DMF or DMSO. The salts ofthe azoles thus formed are dissolved in an aprotic solvent such as DMFor DMSO and treated with a suitable amount of alkylating reagent.

An alternative possibility for the deprotonation of the azolederivatives is, for example, reaction with potassium carbonate in DMF orDMSO.

The reactions are carried out at temperatures below room temperature upto the boiling point of the reaction mixture, preferably between +20° C.and the boiling point of the reaction mixture, for about 1 to 10 hours.

The biphenyl derivatives can be synthesized, for example, starting fromarylboronic acid derivatives by coupling with substituted aryl halidesusing transition metal catalysts, in particular palladium. Correspondingreactions are described by R. B. Miller et al. (Organometallics 1984, 3,1261) or by A. Zuzuki et al. (Synthetic Commun. 11 (7), 513 (1981)).

The sulfonylurethanes of the formula I can be obtained from appropriatesulfonamides of the formula I by reaction with chlorocarbonic acidesters in inert high-boiling solvents such as, for example, toluene attemperatures of about 100° C. or the boiling points of the appropriatesolvents.

Analogously, sulfonyl-sulfonamides can be prepared from the appropriatesulfonamides by reaction with sulfonyl chlorides or sulfamoyl chlorides.

The sulfonamide radical can be prepared by means of Meerwein reaction,if necessary, starting from an amino group. For this, the hydrochlorideof the amine is first diazotized and then reacted with sulfur dioxide inglacial acetic acid in the presence of a copper catalyst. Subsequentaction of ammonia leads to the sulfonamido group.

Alternatively, an appropriate thiophenol can be converted into asulfonamide by oxidation with chlorine and subsequent action of ammonia.

The compounds of the formula (I) according to the invention haveantagonistic action on angiotensin II receptors and can therefore beused for the treatment of angiotensin II-dependent hypertension.Possibilities of application furthermore exist in cardiac insufficiency,cardioprotection, myocardial infarct, cardiac hypertrophy,arteriosclerosis, nephropathy, kidney failure and vascular diseases ofthe brain such as transitory ischemic attacks and stroke.

Renin is a proteolytic enzyme of the aspartylprotease class, which issecreted into the blood circulation by the juxtaglomerular cells of thekidney as a consequence of various stimuli (volume depletion, sodiumdeficiency, β-receptor stimulation). In the blood, it cleaves thedecapeptide angiotensin I from the angiotensinogen excreted from theliver. The former is converted into angiotensin II by the"angiotensin-converting enzyme" (ACE). Angiotensin II plays an essentialrole in blood pressure regulation, as it directly increases the bloodpressure by means of vascular contraction. It additionally stimulatesthe secretion of aldosterone from the adrenal gland and in this wayincreases the extracellular fluid volume via the inhibition of sodiumexcretion, which for its part contributes to an increase in bloodpressure.

Post-receptor actions are inter alia stimulation of phosphoinositolconversion (Ca²⁺ release), activation of protein kinase C) andfacilitation of c-E-dependent hormone receptors.

The affinity of the compounds of the formula I for the angiotensin IIreceptor can be determined by measurement of ¹²⁵ I-angiotensin II or ³H-angiotensin II displacement from receptors on membranes of the zonaglomerulosa of bovine adrenal glands. For this purpose, the preparedmembranes are suspended in buffer at pH 7.4.

Aprotinin, a peptidase inhibitor, is added in order to prevent thedegradation of the radioligand during the incubation. About 14000 cpm ofa tracer having a specific activity of 74 TBq/mmol (available fromAmersham Buchler, Braunschweig, FRG) and a quantity of receptor proteinwhich binds 50% of the tracer are additionally used. The reaction isbegun by addition of 50 μl of membrane suspension to a mixture of 100 μlof buffer+aprotinin, 50 μl of buffer with or without angiotensin II orreceptor antagonist and 50 μl of tracer. After an incubation time of 60minutes at a temperature of 25° C., bound and free radioligand areseparated on a Skatron® cell collector using Whatmann® GFIC filters bymeans of a filtration assay.

Non-specific binding is prevented by treatment of the filter with 0.3%polyethyleneimine pH=10 (Sigma, No. 3143).

The amount of displacement of the radioligand from the receptor isdetermined by measurement of the radioactivity in a gamma scintillationcounter. The IC₅₀ values, which denote the concentration of inhibitorfor displacing 50% of the ligand, are determined according to J. Theor.Biol. 59, 253 (1970). For the compounds of the formula (I) they are inthe range from 1×10⁻⁴ -1×10⁻⁹ M.

Alternatively, the affinity of the compounds of the formula I for theangiotensin II receptor can be determined by measurement of the ¹²⁵I-angiotensin II or ³ H-angiotensin II displacement of receptorpreparations from various organs (liver, lung, adrenal gland, brainetc.).

To this end, the prepared membranes are suspended in an incubationbuffer (20 mm Tris, pH 7.4, containing 135 mM NaCl, 10 mM KCl, 10 mMMgCl₂, 5 mM glucose, 0.2% bovine serum albumin and the proteaseinhibitors PMSF, 0.3 mM, and bacitracin, 0.1 mM) and incubated at 25° C.for 90 min together with the radioactively labeled angiotensin II andvarious concentrations of the compounds to be tested. Bound and freeradioligand are then separated by filtration through micro glass fiberfilters (GF51, Schleicher and Schull) in a cell collector (SKATRON).

The degree of displacement of the radioligand from the receptor by thetest compounds is determined by measurement of the receptor-boundradioactivity on the filters by means of a beta- or gamma-spectrometer.The amount of the displacement of the radioligand from the receptor bythe test compounds is indicated by the IC₅₀, i.e. the concentration ofthe inhibitor which displaces 50% of the bound radioligand from thereceptor. The calculation of the IC₅₀ values is carried out by means ofPC software (LIGAND, G. A. McPherson 1985, Elsevier BIOSOFT, 68 HillsRoad, Cambridge, CB2 1LA, UK.). The IR₅₀ values measured for compoundsof the formula (I) are in the range from 1×10⁻⁵ to 1×10⁻¹¹ M (Table 1which follows, in which the IC₅₀ values are collated for compoundsaccording to the invention).

                  TABLE 1                                                         ______________________________________                                               Example                                                                              IC.sub.50 [nM]                                                  ______________________________________                                                1     5000                                                                    2     8000                                                                    3     1100                                                                    4     1100                                                                    5     16000                                                                   22    2000                                                                    24    800                                                                     25    1400                                                                    29    1.1                                                                     30    2030.0                                                                  31    153.0                                                                   32    3.5                                                                     33    34.0                                                                    34    1.0                                                                     35    50.0                                                                    36    16.0                                                                    37    1.1                                                                     55    8.8                                                                     56    4.6                                                                     57    1100                                                                    58    3.0                                                                     59    1.3                                                                     60    2.2                                                                     61    1.1                                                                     62    3.6                                                                     63    1.3                                                                     64    0.5                                                                     65    1.8                                                                     66    6.9                                                                     67    0.91                                                                    68    12.0                                                                    69    3.2                                                                     70    4.4                                                                     71    2.2                                                                     73    2.5                                                                     76    9.5                                                                     79    5.8                                                                     80    0.69                                                                    81    0.79                                                                    83    0.96                                                                    84    4.3                                                                     85    3.9                                                                     89    1.1                                                                     90    0.69                                                                    92    280.0                                                                   93    3.3                                                                     95    1.8                                                                     98    1.4                                                                     99    26.6                                                                   100    68.5                                                                   101    2.4                                                                    102    2.3                                                                    105    3.0                                                                    107    2.5                                                                    108    0.95                                                                   109    0.6                                                                    110    0.5                                                                    111    2.9                                                                    112    1.5                                                                    113    0.3                                                                    115    0.9                                                                    116    2.4                                                                    117    1.2                                                                    124    1.8                                                                    125    2.8                                                                    127    3.0                                                                    128    5.6                                                                    129    1.5                                                                    134    180.0                                                                  135    5.6                                                                    138    1.7                                                                    139    2.8                                                                    140    8.2                                                                    141    4.4                                                                    144    5.3                                                                    146    40.0                                                                   151    0.4                                                                    152    1.5                                                                    153    0.88                                                                   154    1.8                                                                    155    6.0                                                                    156    4.7                                                                    157    1.4                                                                    159    8.7                                                                    160    0.73                                                                   161    57.0                                                                   162    3.9                                                                    163    3.7                                                                    164    0.86                                                                   165    2.3                                                                    166    1.2                                                                    167    4.0                                                                    168    7.0                                                                    169    2.9                                                                    170    2.7                                                                    171    0.7                                                                    172    0.48                                                                   174    5.1                                                                    179    2.6                                                                    181    1.0                                                                    183    1.7                                                                    185    5.9                                                                    186    6.5                                                                    187    1.2                                                                    190    22.0                                                                   191    21.4                                                                   194    21.7                                                                   195    3.0                                                             ______________________________________                                    

To determine the antagonistic action of the compounds of the formula(I), their effect on the angiotensin II-induced blood pressure rise inanesthetized Sprague-Dawley rats can be measured. Na thiobarbital(Trapanal®, trademark of Byk Gulden, FRG) is used as an anesthetic inthe dose 100 mg/kg J.p. i.v. administration is carried out in thejugular vein. The blood pressure is measured in the carotid artery. Theanimals are first pretreated with pentoliniumtartrate (10 mg/kg i.m.) sothat a lower blood pressure level is achieved (ganglia blockade). ANG II(Hypertensin CIBA) is administered i.v. in the volume 0.1 ml/100 g at 10minute intervals. The dose is 0.5 μg/kg. The compounds of the formula(I) are dissolved in distilled water and administered intravenously orintraduodenally in the doses 0.1 to 1.0 mg/kg, or 10 and 100 mg/kgrespectively.

The compounds of the formula (I) are particularly effective in the rangefrom 0.1-100 mg/kg, preferably 0.1-3 mg/kg.

The invention also relates to pharmaceutical compositions comprising acompound of the formula (I) and other active compounds, such as, forexample, diuretics or non-steroidal anti-inflammatory active compounds.The compounds of the formula (I) can also be used as diagnostics for therenin-angiotensin system.

Pharmaceutical preparations contain an effective amount of the activecompound of the formula (I) and if necessary other active compoundstogether with an inorganic or organic pharmaceutically utilizableexcipient. Administration can be carried out intranasally,intravenously, subcutaneously or orally. The dosage of the activecompound depends on the mammalian species, the body weight, the age andthe manner of administration.

The pharmaceutical preparations of the present invention are prepared ina dissolving, mixing, granulating or coating process known per se.

For a form for oral administration, the active compounds are mixed withthe additives customary therefor such as excipients, stabilizers orinert diluents and brought by means of customary methods into suitableadministration forms such as tablets, coated tablets, hard gelatincapsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholicor oily solutions. Inert excipients which can be used are, for example,gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose,glucose, magnesium stearyl fumarate or starch, in particular maizestarch. The preparation in this case can be dry and moist granules.Suitable oily excipients or solvents are, for example, vegetable oranimal oils, such as sunflower oil and cod liver oil.

For subcutaneous or intravenous administration, the active compounds ortheir physiologically tolerable salts are brought into solutions,suspensions or emulsions, if appropriate with the substances customarytherefor such as solubilizers, emulsifiers or other auxiliaries.Suitable solvents are, for example, water, physiological saline solutionor alcohols, such as ethanol, propanediol or glycerol, and sugarsolutions such as glucose or mannitol solutions or mixtures of saidsolvents.

    ______________________________________                                        List of abbreviations:                                                        ______________________________________                                        DMF           N,N-dimethylformamide                                           NBS           N-bromosuccinimide                                              AIBN          α,α-azobisisobutyronitrile                          EI            electron impact                                                 DCI           desorption-chemical ionization                                  RT            room temperature                                                EA            ethyl acetate (EtOAc)                                           DIP           diisopropyl ether                                               MTB           methyl tertiary butyl ether                                     m.p.          melting point                                                   HEP           n-heptane                                                       DME           dimethoxyethane                                                 FAB           fast atom bombardment                                           CH.sub.2 Cl.sub.2                                                                           dichloromethane                                                 ______________________________________                                    

The invention is illustrated by the following examples:

EXAMPLE 1

Synthesis of1-[(2'-phenylaminocarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-chloroimidazole-5-carboxaldehyde##STR17##

a) Preparation of 4'-methylbiphenyl-2-amine

3 g of Raney nickel are added to 23.9 g (0.112 mol) of4'-methyl-2-nitrobiphenyl (R. B. Muller and S. Dugar, Organometallics1984, 3, 1261) in 50 ml of methanol and the mixture is hydrogenatedunder normal pressure at room temperature until the theoretical amountof H₂ has been absorbed. The catalyst is then removed by filtration andthe filtrate is concentrated. Chromatography on SiO₂ (500 g) usingEA/HEP(1:6) as the eluent yields 19 g of the title compound as an oil(92.5%)

R_(f) (EA/HEP 1:4)=0.3 MS(EI)=183 (M⁺)

b) 4'-Methylbiphenyl-2-ammonium hydrochloride

10 g of compound 1a) are dissolved in 50 ml of 6N HCl and 100 ml ofdioxane. Removal of the solvent by distillation yields the titlecompound, which is used without further purification.

c) 4'-Methylbiphenyl-2-sulfonamide

7.9 g (114 mmol) of sodium nitrite are added at -10° C. to a suspensionof 31 g (140 mmol) of compound 1b) in 200 ml of 6N HCl, a clear solutionbeing formed. This is added at 0° C. to a solution containing 200 ml ofglacial acetic acid, saturated with SO₂, 17 g of CuCl₂.H₂ O and 25 ml ofH₂ O. The mixture is then allowed to come to room temperature and isstirred at this temperature for 2 hours. 250 ml of EA are then added,the phases are separated and the organic phase is dried using magnesiumsulfate. Concentration yields an oil, which is dissolved in 300 ml ofacetone. 150 ml of 25% strength ammonia are then added and the mixtureis stirred for 2 hours. It is then concentrated and 500 ml of EA areadded. The EA phase is washed 1× with H₂ O, dried using MgSO₄ andconcentrated. Chromatography on SiO₂ using EA/HEP(1:1) yields the titlecompound (4.6 g).

R_(f) (EA/HEP 1:1)=0.25 MS(DCI)=248 (M⁺ +H) M.p.: 122° C.

d) 4'-Methylbiphenyl-2-N,N-dimethylaminoformylsulfonamide

4.6 g (18.6 mmol) of compound 1c) and 2.5 g (19.3 mmol) ofN,N-dimethylformamide dimethyl acetal in 30 ml of DMF are stirred atroom temperature for 2 hours, then 100 ml of H₂ O are added and theprecipitate formed is filtered off with suction and dried in the air,4.2 g of the title compound being obtained

R_(f) (EA/HEP 1:1)=0.2 MS (DCI)=303 (M⁺ +H)

e) 4'-Bromomethylbiphenyl-2-N,N-dimethylaminoformylsulfonamide

150 mg of benzoyl peroxide are added to 3.76 g (13.5 mmol ) of thecompound 1d) and 2.4 g of NBS (13.5 mmol) in 50 ml of chlorobenzene.After 4 hours under reflux, the mixture is concentrated, 50 ml of EA areadded and the EA phase is washed once with 10% strength Na₂ SO₃ solutionand once with HaO. After drying with Na₂ SO₄, it is concentrated andchromatographed on SiO₂ (eluent EA/HEP 2:1). 1.2 g of the title compoundare obtained.

R_(f) (EA/HEP 2:1)=0.23 MS (DCI)=381, 383 (M⁺ +H)

f) 2-n-Butyl-4-chloro-5-formylimidazole

305 ml of a 1M (NH₄)₂ Ce(NO₃)₆ solution in H₂ O are added slowly at10°-15° C. to 20 g (0.106 mol) of2-n-butyl-n-4-chloro-5-hydroxymethylimidazole (prepared according toEP-A 253,310) in 350 ml of glacial acetic acid. After 2.5 h at roomtemperature, the pH is adjusted to 4 using 2N KOH (20° C. during theaddition of the base). The mixture is then extracted 4× using 500 ml ofCH₂ Cl₂ each time and the combined organic extracts are washed 3× with300 ml of saturated aqueous NaHCO₃ solution each time, dried with Na₂SO₄ and concentrated, the title compound being obtained as a colorlesssolid (18 g, 92%).

M.p.:=90° C. R_(f) (DIP/MTB 1:1)=0.5

g)1-[(2'-N,N-Dimethylaminoformylsulfonamidobiphenyl-4-yl)methyl]-2-n-butyl-4-chloroimidazole-5-carboxaldehyde

690 mg (1.98mmol) of compound 1e), 370 mg (1.98 mmol) of compound 1f)and 270 mg (1.98 mmol) of potassium carbonate are stirred in DMF (10 ml)at room temperature for 2 hours. 50 ml of EA are then added and themixture is washed twice with H₂ O. The organic phase is dried (Na₂ SO₄)and concentrated. Chromatography on SiO₂ using EA/HEP (2:1) as an eluentyields the title compound (380 mg; 40%)

R_(f) (EA/HEP 2:1)=0.15 MS (DCI)=487 (M⁺ +H)

h)1-[(2'-Sulfonamidobiphenyl-4-yl)methyl]-2-n-butyl-4-chloroimidazole-5-carboxaldehyde

280 mg (0.58 mmol) of compound 1 g) in 7 ml of methanol and 14 ml of H₂O are treated with 110 mg (2.88 mmol) of sodium hydroxide and themixture is heated to boiling for 4 hours. After cooling to roomtemperature, the mixture is adjusted to approximately pH 6 using 4 N HCland is extracted 3 times using 30 ml of EA, and the EA phases are dried(Na₂ SO₄) and concentrated, 190 mg of the title compound being obtained.

R_(f) (EA/HEP 2:1)=0.45 MS (DCI)=432 (M⁺ +H)

i)1-[(2'-Phenylaminocarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-chloroimidazole-5-carboxaldehyde

730 mg (1.69 mmol) of compound 1b) are heated to 80° C. in 10 ml ofphenyl isocyanate. After 4 hours, the mixture is concentrated andchromatographed on SiO₂ (eluent EA/HEP (251)), 400 mg of the titlecompound being obtained.

R_(f) (EA/HEP 2:1)=0.15 MS (DCI)=551 (M⁺ +H)

Alternative preparation of compound 1d(4'-Methyl-2-N,N-dimethylaminoformylsulfonamide)

First 420 mg of Pd(OAc)₂ and then 5.66 g (41.9 mmol) of 4-tolylboronicacid in 100 ml of ethanol are added under argon to 11 g (37.9 mmol) of2-N,N-dimethylaminoformylsulfonamidobromobenzene (prepared from2-bromoaniline analogously to 1b-1d), 1 g of triphenylphosphine, 8 g ofNa₂ CO₃ in 150 ml of toluene and 40 ml of H₂ O. The mixture is thenheated to boiling for 4 h. It is then concentrated and taken up in 500ml of ethyl acetate and 500 ml of H₂ O. The resultant precipitate isfiltered off and characterized as the title compound. The ethyl acetatephase is separated off, dried (Na₂ SO₄) and concentrated. Chromatographyon SiO₂ using ethyl acetate yields a further amount of title compound(altogether 7.6 g=66%).

Alternative preparation of 2-bromobenzenesulfonamide (to theintermediate stage analogous to 1c)

Cl₂ gas is introduced at 0°-10° C. for 30 min into 4.7 g of2-bromothiophenol in 60 ml of H₂ O. The mixture is then stirred at 0° C.for 30 min and air is subsequently blown through the solution withoutcooling for 30 min. After addition of 60 ml of acetone and cooling againto 0° C., 10 ml of saturated NH₄ OH solution are slowly added dropwise.After a further 30 min, the pH of the solution is adjusted to the value3 using 4 n HCl and the product is obtained by filtration.

Yield 4.5 g (77%) M.p.=190°-191° C. R_(f) (EA/H 1:1)=0.4

EXAMPLE 2

The synthesis of 1-[(2'-n-propylaminocarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-chloroimidazole-5-carboxaldehydewas carried out analogously to Example 1

R_(f) (EA)=0.6 MS (FAB)=517 (M⁺ +H) ##STR18##

EXAMPLE 3

Synthesis of1-[(2'-pyridyl-2-aminocarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-chloroimidazole-5-carboxaldehyde##STR19##

a)1-[(2'-Ethoxycarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-chloroimidazole-5-carboxaldehyde0.48 ml (5.1 mmol) of ethyl chloroformate is added to 1.1 g (2.5mmol) ofcompound 1 h) and 0.78 g (5.6 mmol) of potassium carbonate in 20 ml ofdry DME. After 1 hour, the mixture is allowed to cool to roomtemperature and is treated with 50 ml of 10% strength KH₂ PO₄ solution.After extraction using EA, the mixture is dried using Na₂ SO₄ andconcentrated. Chromatography on SiO₂ using EA/HEP (2:1) as the eluentyields 840 mg of title compound.

R_(f) (EA/HEP 2:1)=0.32 MS (DCI)=504 (M⁺ +H)

b)1-[(2'-pyridyl-2-aminocarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-chloroimidazole-5-carboxaldehyde

150 mg (0.3 mmol) of compound 3a) and 28.5 mg (0.3 mmol) of2-aminopyridine are heated to boiling for 2 hours in 8 ml of drytoluene. The mixture is then concentrated and chromatographed on SiO₂(eluent EA), 34 mg of the title compound being obtained.

R_(f) (EA/methanol 10:1)=0.4 MS (FAB)=552 (M⁺ +1)

The compounds of Examples 4-39 can be synthesized analogously to Example3.

These compounds have the following formula (A) ##STR20##

                  TABLE 2                                                         ______________________________________                                               MS (FAB;  Substitution                                                 Example                                                                              M.sup.+  + H)                                                                           position  R                                                  ______________________________________                                         4  (16)   553       3'   (2')                                                 5  (17)   543       3'   (2')                                                                                ##STR21##                                      6  (18)   558       3'   (2')                                                                                ##STR22##                                      7  (19)   559       3'   (2')                                                                                ##STR23##                                      8  (20)   597       3'   (2')                                                                                ##STR24##                                      9  (21)   541       3'   (2')                                                                                ##STR25##                                     10  (22)   596       3'   (2')                                                                                ##STR26##                                     11  (23)   596       3'   (2')                                                                                ##STR27##                                     12  (24)   569       3'   (2')                                                                                ##STR28##                                     13  (25)   569       3'   (2')                                                                                ##STR29##                                     14  (26)   631       3'   (2')                                                                                ##STR30##                                     15  (27)   631       3'   (2')                                                                                ##STR31##                                     28         552       3'                                                                                       ##STR32##                                     29         580       2'                                                                                       ##STR33##                                     30         586       2'                                                                                       ##STR34##                                     31         584       2'                                                                                       ##STR35##                                     32         572       2'                                                                                       ##STR36##                                     33         581       2'                                                                                       ##STR37##                                     34         595       2'                                                                                       ##STR38##                                     35         565       2'                                                                                       ##STR39##                                     36         565       2'                                                                                       ##STR40##                                     37         579       2'                                                                                       ##STR41##                                     38         583       2'                                                                                       ##STR42##                                     39         589       2'                                                                                       ##STR43##                                     ______________________________________                                    

EXAMPLE 40

Synthesis of1-[(2'phenylaminocarbonylaminosulfonylbiphenyl-4-yl)-methyl]-2-n-butyl-4-chloro-5-hydroxymethylimidazole100 mg (0.18 mmol) of compound 1) are dissolved in 5 ml of ethanol andthe solution is treated at room temperature with 10 mg (0.27 mmol) ofsodium borohydride. After 20 hours, 20 ml of 5% strength sodium hydrogensulfate solution are added and the mixture is extracted 3× using EA. Theorganic phase is dried with Na₂ SO₄ and concentrated. Chromatography onSiO₂ using EA/HEP (3:1) yields 55 mg of the title compound.

R_(f) (EA/HEP 3:1)=0.25 MS (DCI)=553 (M⁺ +H)

The compounds (see formula B) of Examples 41-54 were synthesizedanalogously to Example 40 from the compounds of Examples 2, 3 and 16-27(Table 3).

                  TABLE 3                                                         ______________________________________                                         ##STR44##                    (B)                                                       MS                                                                  Example   (FAB; M.sup.+  + H)                                                                        R                                                      ______________________________________                                        41        519          n-propyl                                               42        554                                                                                         ##STR45##                                             43        555                                                                                         ##STR46##                                             44        545                                                                                         ##STR47##                                             45        560                                                                                         ##STR48##                                             46        561                                                                                         ##STR49##                                             47        599                                                                                         ##STR50##                                             48        543                                                                                         ##STR51##                                             49        598                                                                                         ##STR52##                                             50        598                                                                                         ##STR53##                                             51        571                                                                                         ##STR54##                                             52        571                                                                                         ##STR55##                                             53        633                                                                                         ##STR56##                                             54        633                                                                                         ##STR57##                                             ______________________________________                                    

EXAMPLE 55

Preparation of1-[(2'-allylaminocarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-chloroimidazole-5-carboxaldehyde##STR58##

730 mg (1.69 mmol) of compound 1 h) are heated at 80° C. in 10 ml ofallyl isocyanate. After 4 hours, the mixture is concentrated andchromatographed on SiO₂ (eluent EA/HEP (2:1)), 400 mg of the titlecompound being obtained.

R_(f) (EA/HEP 2:1)=0.15 MS (FAB)-515 (M⁺ +H)

EXAMPLE 56

Preparation of1-[(2'-allylaminocarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylicacid ##STR59##

a) Ethyl 2-amino-2-cyanoacetate

119 g of sodium dithionite are added in portions (15 min) at roomtemperature to 35 g (0.246 mol) of ethyl 2-cyanoglyoxylate-2-oxime in350 ml of H₂ O and 280 ml of saturated sodium hydrogen carbonatesolution. The mixture is then warmed at 35° C. for 1 hour; it is thensaturated with NaCl and extracted 5 times with dichloromethane. Afterdrying with calcium chloride, the organic phase is concentrated. 11.8 gof the title compound are obtained as an oil.

R_(f) (CH₂ Cl₂ /CH₃ OH 9:1)=0.6

b) Ethyl 2-cyano-2-n-butylcarbonylaminoacetate

3.39 ml (28.09 mmol) of valeryl chloride in 5 ml of CH₂ Cl₂ are addeddropwise at -5° C. to 0° C. to 3.6 g (28.09 mmol) of compound 56a) in 50ml of dry CH₂ Cl₂ and 2.3 ml (28.09 mmol) of pyridine. The mixture isthen stirred at room temperature for 1 hour. The organic phase is thenwashed 3 times using H₂ O and once using saturated NaCl solution, driedusing calcium chloride and concentrated. Crystallisation from DIP yields1.7 g of the title compound.

R_(f) (CH₂ Cl₂ /CH₃ OH 9:1)=0.35 M.p.: 87° C.

c) Ethyl 3-amino-2-n-butylcarbonylaminomethylthioacrylate

2 ml (27.26 mmol) of condensed methylthiol are added at room temperatureto 2.9 g (13.67 mmol) of compound 56b) and 0.19 ml (1.36 mmol) oftriethylamine in 60 ml of absolute ethanol. After 3 days, a further 0.5ml of methylthiol is added. After another 24 hours at room temperature,a further 0.5 ml of methylthiol and 0.19 ml of triethylamine are addedby syringe and the mixture is stirred at room temperature for another 24hours. The solvent is then removed and the residue is crystallized fromDIP, 2.4 g of the title compound being obtained.

R_(f) (CH₂ Cl₂ /EA 4:1)=0.3 M.p.: 120° C.

d) Ethyl 2-n-butyl-4-methylthioimidazole-5-carboxylate

2.44 g (20.0 mmol) of 4-dimethylaminopyridine in 12 ml of CH₂ Cl₂ areadded dropwise at -78° C. to 4.17 g (20.0 mmol) of phosphoruspentachloride in 20 ml of CH₂ Cl₂. After 5 min, 2.42 g (10.0 mmol) ofcompound 56c) are added dropwise in 25 ml of CH₂ Cl₂. The mixture isthen allowed to come to room temperature and diluted with 30 ml of CH₂Cl₂. After 2 hours, 300 ml of 1N sodium hydrogen carbonate solution areadded with ice-cooling and the mixture is stirred for 1 hour. The phasesare then separated, the aqueous phase is extracted 3 times using EA andthe combined organic phases are dried using calcium chloride.Chromatography on SiO₂ with CH₂ Cl₂ /EA (9:1)

R_(f) (CH₂ Cl₂ /EA 9:1)=0.6 MS (DCI)=243 (M⁺ +H)

e) Ethyl1-[(2'-sulfonamidobiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylate

15 ml of conc. HCl are added to 1.35 g (2.5 mmol) of ethyl1-[(2'-N,N-dimethylaminoformylsulfonamidobiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylate[prepared from Example 56d) and Example 1e) analogously to Example 1g)]in 30 ml of methanol. After 90 min under reflux, the mixture is allowedto cool to room temperature and is adjusted to pH=5-6 using 2N NaOHsolution. It is then extracted 3 times using 100 ml of EA each time, andthe organic extracts are dried using Na₂ SO₄ and concentrated, the titlecompound being obtained as a foam which is employed without furtherpurification for the next reaction step.

R_(f) (EA/HEP 1:1)=0.2 MS (FAB)=488 (M+H) f) The title compound 56 isobtained by stirring 120 mg of ethyl1-[(2'-allylaminocarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylate(obtainable analogously to Example 55)) at room temperature for 4 daysin 10 ml of ethanol and 1 ml of 2 N sodium hydroxide solution. Themixture is then concentrated, H₂ O is added and the mixture is adjustedto pH=4 using 1N HCl, the title compound precipitating and beingisolated by filtration.

R_(f) (EA/MeOH 10:1)=0.1 MS (FAB)=543 (M+H)

EXAMPLE 57

Synthesis of1-[(2'-pyridylethyl-2-aminocarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazol-4-carboxylicacid ##STR60##

a) Ethyl1-[(2'-ethoxycarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylate

1.21 g (2.5 mmol) of compound 56e) and 0.78 g (5.6 mmol) of potassiumcarbonate in 20 ml of dry DME are heated to boiling and 0.48 ml (5.1mmol) of ethyl chloroformate is added. After 1 hour, the mixture isallowed to cool to room temperature and 50 ml of 10% strength KH₂ PO₄solution are added. After extraction with EA, the extract is dried usingNa₂ SO₄ and concentrated. Chromatography on SiO₂ using EA/HEP (2:1) asthe eluent yields 840 mg of the title compound.

R_(f) (EA/HEP 2:1)=0.5 MS (DCI)=559 (M⁺ +H)

b) Ethyl1-[(2'-pyridylethyl-2-aminocarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylate

168 mg (0.3 mmol) of compound 57a) and 37 mg (0.3 mmol) of2-(2-aminoethyl)pyridine are heated to boiling for 2 hours in 8 ml ofdry toluene. The mixture is then concentrated and chromatographed onSiO₂ (eluent EA), 34 mg of the title compound being obtained.

R_(f) (EA)=0.15 MS (FAB)=636 (M⁺ +H)

c) The title compound 57 is obtained analogously to 56f) R_(f) (EA/MeOH5:1)=0.1 MS (FAB)=608 (M+H)

The compounds of the following Table 4 can be synthesized in a manneranalogous to that in Example 57.

These compounds have the formula (C)

                                      TABLE 4                                     __________________________________________________________________________     ##STR61##                              (C)                                        MS                                                                       Example                                                                            (FAB; M.sup.+  + H)                                                                    R  R'                R"                                         __________________________________________________________________________     58  571      C.sub.2 H.sub.5                                                                   ##STR62##        H                                           59  585      H                                                                                 ##STR63##        H                                           60  599      H                                                                                 ##STR64##        H                                           61  583      H                                                                                 ##STR65##                                                                                       ##STR66##                                  62  611      H                                                                                 ##STR67##        H                                           63  668      H                                                                                 ##STR68##        H                                           64  541      H                                                                                 ##STR69##        H                                           65  636      C.sub.2 H.sub.5                                                                   ##STR70##        H                                           66  635      C.sub.2 H.sub.5                                                                   ##STR71##        H                                           67  607      H                                                                                 ##STR72##        H                                           68  659      C.sub.2 H.sub.5                                                                   ##STR73##        H                                           69  645      C.sub.2 H.sub.5                                                                   ##STR74##        H                                           70  657      C.sub.2 H.sub.5                                                                   ##STR75##        H                                           71  603      C.sub.2 H.sub.5                                                                  CH.sub.2CO.sub.2 CH.sub.3                                                                       H                                           72  693      C.sub.2 H.sub.5                                                                   ##STR76##        H                                           73  621      C.sub.2 H.sub.5                                                                   ##STR77##        H                                           74  703      C.sub.2 H.sub.5                                                                   ##STR78##        H                                           75  561      H                                                                                 ##STR79##        H                                           76  649      C.sub.2 H.sub.5                                                                   ##STR80##        H                                           77  663      C.sub.2 H.sub.5                                                                   ##STR81##        H                                           78  653      C.sub.2 H.sub.5                                                                   ##STR82##                                                                                       ##STR83##                                  79  675      H                                                                                 ##STR84##        H                                           80  593      H                                                                                 ##STR85##        H                                           81  621      H                                                                                 ##STR86##        H                                           82  635      H                                                                                 ##STR87##        H                                           83  623      H                                                                                 ##STR88##        H                                           84  651      C.sub.2 H.sub.5                                                                   ##STR89##        H                                           85  651      C.sub.2 H.sub.5                                                                   ##STR90##        H                                           86  627      C.sub.2 H.sub.5                                                                   ##STR91##        H                                           87  611      C.sub.2 H.sub.5                                                                   ##STR92##                                                                                       ##STR93##                                  88  635      C.sub.2 H.sub.5                                                                   ##STR94##        H                                           89  653      H                                                                                 ##STR95##        H                                           90  623      H                                                                                 ##STR96##        H                                           91  639      C.sub.2 H.sub.5                                                                   ##STR97##        H                                           92  681      C.sub.2 H.sub.5                                                                   ##STR98##        H                                           93  623      H                                                                                 ##STR99##        H                                           94  611      H                                                                                 ##STR100##       H                                           95  635      C.sub.2 H.sub.5                                                                   ##STR101##       H                                           96  625      H                                                                                 ##STR102##                                                                                      ##STR103##                                 97  561      H  CH.sub.2CO.sub.2 H                                                                              H                                           98  651      H                                                                                 ##STR104##       H                                           99  607      C.sub.2 H.sub.5                                                                   ##STR105##       H                                          100  625      C.sub.2 H.sub.5                                                                   ##STR106##       H                                          101  597      H                                                                                 ##STR107##       H                                          102  579      H                                                                                 ##STR108##       H                                          103  677      C.sub.2 H.sub.5                                                                   ##STR109##       H                                          104  649      H                                                                                 ##STR110##       H                                          105  573      C.sub.2 H.sub.5                                                                  (CH.sub.2).sub.2CH.sub.3                                                                        H                                          106  545      H  (CH.sub.2).sub.2CH.sub.3                                                                        H                                          107  616      H                                                                                 ##STR111##       H                                          108  614      H                                                                                 ##STR112##       H                                          109  557      H                                                                                 ##STR113##       H                                          110  585      C.sub.2 H.sub.5                                                                   ##STR114##       H                                          111  642      H                                                                                 ##STR115##       H                                          112  594      H                                                                                 ##STR116##       H                                          113  594      H                                                                                 ##STR117##       H                                          114  638      C.sub.2 H.sub.5                                                                   ##STR118##       H                                          115  594      H                                                                                 ##STR119##       H                                          116  628      H                                                                                 ##STR120##       H                                          117  628      C.sub.2 H.sub.5                                                                   ##STR121##       H                                          118  628      C.sub.2 H.sub.5                                                                   ##STR122##       H                                          119  644      C.sub.2 H.sub.5                                                                   ##STR123##       H                                          120  600      H                                                                                 ##STR124##       H                                          121  642      C.sub.2 H.sub.5                                                                   ##STR125##       H                                          122  614      H                                                                                 ##STR126##       H                                          123  651      C.sub.2 H.sub.5                                                                   ##STR127##       H                                          124  623      H                                                                                 ##STR128##       H                                          125  623      H                                                                                 ##STR129##       H                                          126  661      C.sub.2 H.sub.5                                                                   ##STR130##       H                                          127  633      H                                                                                 ##STR131##       H                                          128  665      C.sub.2 H.sub.5                                                                   ##STR132##       H                                          129  637      H                                                                                 ##STR133##       H                                          130  600      H                                                                                 ##STR134##       H                                          131  642      C.sub.2 H.sub.5                                                                   ##STR135##       H                                          132  665      C.sub.2 H.sub.5                                                                   ##STR136##       H                                          133  637      H                                                                                 ##STR137##       H                                          134  667      C.sub.2 H.sub.5                                                                   ##STR138##       H                                          135  639      H                                                                                 ##STR139##       H                                          136  664      C.sub.2 H.sub.5                                                                   ##STR140##       H                                          137  636      H                                                                                 ##STR141##       H                                          __________________________________________________________________________

The compounds of the following Table 5 can be synthesized analogously toExample 57.

These compounds have the following formula (D)

                  TABLE 5                                                         ______________________________________                                         ##STR142##                   (D)                                                    MS (FAB;                                                               Example                                                                              M.sup.+  + H)                                                                           R       R'                                                   ______________________________________                                        138    581       C.sub.2 H.sub.5                                                                        ##STR143##                                          139    553       H                                                                                      ##STR144##                                          140    601       C.sub.2 H.sub.5                                                                        ##STR145##                                          141    585       C.sub.2 H.sub.5                                                                        ##STR146##                                          142    557       H                                                                                      ##STR147##                                          143    573       H                                                                                      ##STR148##                                          144    617       C.sub.2 H.sub.5                                                                        ##STR149##                                          145    603       C.sub.2 H.sub.5                                                                        ##STR150##                                          146    714       C.sub.2 H.sub.5                                                                        ##STR151##                                          147    589       H                                                                                      ##STR152##                                          148    686       H                                                                                      ##STR153##                                          149    575       H                                                                                      ##STR154##                                          ______________________________________                                    

EXAMPLE 150

Preparation of1-{[(2'-benzoyloxycarbonylaminosulfonyl)biphenyl-4-yl]methyl}-2-n-butyl-4-chloroimidazol-5-carbaldehyde##STR155##

The title compound 150 is obtained by heating 215 mg (0.5 mol) ofcompound 1 h, 71.3 μl (0.5 mmol) of benzyl chloroformate and 70 mg (0.5mmol) of K₂ CO₃ in 10 ml of DMF (anhydrous) under reflux for 1.5 h. Themixture is then concentrated, 100 ml of EA are added and it is extractedonce each with 40 ml of NaHSO₄ solution and NaCl solution. The organicphase is dried over Na₂ SO₄ and concentrated on a rotary evaporator.Chromatography using MTB yields 120 mg (42%) of the title compound 150,m.p.=56° C.

R_(f) (MTB)=0.20 MS (FAB)=566 (M⁺ +H)

The compounds of the following Table 6 can be synthesized analogously toExamples 150 and 57a.

These compounds have the following formula (E)

                                      TABLE 6                                     __________________________________________________________________________     ##STR156##                         (E)                                            MS                                                                       Example                                                                            (FAB; M.sup.+  + H)                                                                    R    R'              R"                                         __________________________________________________________________________    151  674      OC.sub.2 H.sub.5                                                                   CH.sub.2CH.sub.2Ph                                                                            SMe                                        152  646      OH   CH.sub.2CH.sub.2Ph                                                                            SMe                                        153  558      OH   CH.sub.2CH.sub.2CHCH.sub.2                                                                    SMe                                        154  556      OH   CH.sub.2CH.sub.2CCH                                                                           SMe                                        155  558      OH                                                                                  ##STR157##     SMe                                        156  618      OC.sub.2 H.sub.5                                                                   CH.sub.2CH.sub.2O-i-Pr                                                                        SMe                                        157  590      OH   CH.sub.2CH.sub.2O-i-Pr                                                                        SMe                                        158  666      OC.sub.2 H.sub.5                                                                   CH.sub.2CH.sub.2OCH.sub.2Ph                                                                   SMe                                        159  628      OC.sub.2 H.sub.5                                                                    ##STR158##     SMe                                        160  600      OH                                                                                  ##STR159##     SMe                                        161  648      OC.sub.2 H.sub.5                                                                   CH.sub.2CHCHPh  SMe                                        162  620      OH   CH.sub.2CHCHPh  SMe                                        163  628      OC.sub.2 H.sub.5                                                                    ##STR160##     SMe                                        164  600      OH                                                                                  ##STR161##     SMe                                        165  572      OH   CH.sub.2CHC(CH.sub.3).sub.2                                                                   SMe                                        166  558      OH   CH.sub.2C(CH.sub.3)CH.sub.2                                                                   SMe                                        167  572      OH   CH.sub.2CH.sub.2CH.sub.2CHCH.sub.2                                                            SMe                                        168  598      OH                                                                                  ##STR162##     SMe                                        169  556      OH   CH.sub.2CCCH.sub.3                                                                            SMe                                        170  560      OC.sub.2 H.sub.5                                                                   CH.sub.2CH.sub.3                                                                              SMe                                        171  532      OH   CH.sub.2CH.sub.3                                                                              SMe                                        172  638      OH   CH.sub.2CH.sub.2OCH.sub.2Ph                                                                   SMe                                        173  600      OH                                                                                  ##STR163##     SMe                                        174  584      OC.sub.2 H.sub.5                                                                   CH.sub.3        SMe                                        175  556      OH   CH.sub.3        SMe                                        176  611      H                                                                                   ##STR164##     Cl                                         177  612      H                                                                                   ##STR165##     Cl                                         __________________________________________________________________________

EXAMPLE 178

Preparation of ethyl1-[(2'-dimethylsulfamoylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylate##STR166##

The title compound 178 is obtained by heating 244 mg (0.5 mmol) ofcompound 56 e), 108 μl (1.0 mmol) of sulfamoyl chloride and 140 mg (1.0mmol) of K₂ CO₃ in 10 ml of DME (anhydrous) to reflux for 5 days. Themixture is diluted with 50 ml of EA and washed using 50 ml of KHSO₄ /H₂SO₄ (pH=1.0). The organic phase is dried over Na₂ SO₄ and concentratedon a rotary evaporator. Chromatography with EA yields 69 mg (23%) of acolorless oil.

R_(f) (EA)=0.15 MS (FAB)=617 (M⁺ +Na)

EXAMPLE 179

Preparation of1-[1-(2'-dimethylsulfamoylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylicacid ##STR167##

50 mg (84 μmol) of the title compound of Example 178 and 0.84 ml of 1NNaOH are dissolved in 3 ml of ethanol and stirred at RT for 2 days. Theethanol is distilled off, 5 ml of H₂ O are added and the mixture isadjusted to pH=2 using HCl. The precipitate is washed twice with 1 ml ofwater and dried in vacuo. 33 mg (70%) of a colorless powder areobtained.

R_(f) (EA/methanol 5:1)=0.11 MS (FAB)=567 (M⁺ +H)

EXAMPLE 180

Ethyl1-[(2'-allyloxycarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylate##STR168##

244 mg (0.5 mmol) of the compound 56 e), 106 μl (1.0 mmol) of allylchloroformate and 140 mg (1.0 mmol) of K₂ CO₃ are boiled under refluxfor 1 h. 50 ml of 10% strength KHSO₄ solution are then added and themixture is extracted 3 times using 50 ml of EA each time. The organicphase is dried over Na₂ SO₄ and evaporated. Chromatography using MTB/DIP1:1 yields 115 mg (40%) of a colorless oil.

R_(f) (MTB/DIP 1:1)=0.15 MS (FAB): 572 (M⁺ +H)

EXAMPLE 181

Synthesis of1-[(2'-allyloxycarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylicacid

95 mg (0.17 mmol) of the compound 180 are hydrolyzed as described underExample 179.30 mg (33%) of a colorless foam are obtained.

R_(f) (EA/MeOH 10:1)=0.1 MS (FAB)=544

EXAMPLE 182

Ethyl1-[(2'-benzyloxycarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylate##STR169##

The title compound is synthesized analogously to Example 180.

R_(f) (MTB/DIP 1:1)=0.15 MS (FAB)=622 (M⁺ +H)

EXAMPLE 183

1-[(2'-Benzyloxycarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylicacid ##STR170##

The title compound is synthesized analogously to Example 181.

R_(f) (EA/MeOH 10:1)=0.1 MS (FAB)=594 (M⁺ +OH)

EXAMPLE 184

1-{[2'-Allylaminocarbonylaminosulfonyl)biphenyl-4-yl-methyl}-2-n-butyl-4-methoxyimidazole-5-carbaldehyde##STR171##

a)1-[2'-Sulfonamidobiphenyl-4-yl)methyl]-2-n-butyl-4-methoxyimidazole-5-carbaldehyde

215 mg (0.5 mmol) of compound 1 h) and 1.5 mol of 1N NaOH are boiledunder reflux in 10 ml of methanol for 19 h. The methanol is thenconcentrated on a rotary evaporator, and the mixture is adjusted to pH=2using NaHSO₄ solution and extracted 3 times using 50 ml of EA each time.The organic phase is dried over Na2SO₄ and concentrated on a rotaryevaporator. Chromatography using MTB/DIP (1:1) yields 170 mg (80%) ofthe title compound, m.p.:=189° C.

R_(f) (MTB/DIP 1:1)=0.19 MS (DCI)=428 (M⁺ +H)

b) The title compound 184 is obtained by boiling under reflux 150 mg(0.35 mmol) of compound 184a) and 3 ml of allyl isocyanate for 5 h. Themixture is then concentrated on a rotary evaporator and chromatographedusing EA. 60 mg (34%) of a colorless foam are obtained.

R_(f) (EA)=0.34 MS (FAB)=511 (M⁺ +H)

EXAMPLE 185

1-{[(2'-Ethoxycarbonylaminosulfonyl)biphenyl-4-yl]-methyl}-2-n-butyl-4-methoxyimidazole-5-carbaldehyde##STR172##

1.0 g (2.34 mmol) of compound 184a) is dissolved in 50 ml of acetone(anhydrous) and 650 mg of K₂ CO₃ are added. The mixture is heated toreflux, then 0.45 ml of ethyl chloroformate is slowly added by syringeat this temperature. The mixture is heated under reflux for a further 4h and then concentrated on a rotary evaporator. The residue is acidifiedto pH=2 using NaHSO₄ solution, then extracted 3 times with 100 ml of EAeach time. The extract is dried over Na₂ SO₄ and then concentrated on arotary evaporator, and the residue is chromatographed using MTB/DIP/HOAc(15:83:2). The oil obtained can be crystallized using diethyl ether. 550mg of colorless crystals m.p. 134° C. are obtained.

R_(f) (MTB)=0.24 MS (FAB)=500 (M⁺ +H)

EXAMPLE 186

1-{[(2'-Benzyloxycarbonylaminosulfonyl)biphenyl-4-]methyl}-2-n-butyl-4-methoxyimidazole-5-carbaldehyde##STR173##

Example 186 is synthesized analogously to Example 185.

R_(f) (MTB)=0.16 MS (FAB)=562 (M⁺ +H)

EXAMPLE 187

Ethyl1-{[(2'-benzylaminocarbonylaminosulfonyl)biphenyl-4-yl]methyl}-2-n-butylimidazole-5-carboxylate##STR174##

A catalytic amount of Pd/C is added to 150 mg (0.24 mmol) of compoundExample 73, dissolved in 50 ml of MeOH and 5 ml of HOAc. The mixture isstirred at room temperature for 12 h in an H₂ atmosphere. The mixture isthen concentrated on a rotary evaporator and chromatographed using EA.30 mg (22%) of a colorless foam are obtained.

R_(f) (EA)=0.42 MS (FAB)=575 (M⁺ +H)

EXAMPLE 188

Ethyl1-{[(2'-ethoxycarbonylaminosulfonyl)biphenyl-4-yl]methyl}-2-n-butylimidazole-5-carboxylate##STR175##

About 200 mg of Raney nickel are added to 300 mg (0.5 mmol) of compound57 a, dissolved in 10 ml of EtOH. The mixture is heated under reflux for10 h, a further 200 mg of Raney nickel are added and the mixture isheated under reflux for a further 5 h. The catalyst is filtered off andthe solvent is concentrated on a rotary evaporator. The residue ischromatographed using MTB and 50 mg (18%) of a colorless foam areobtained.

R_(f) (EA)=0.27 MS (FAB)=514 (M⁺ +H)

EXAMPLE 189

Ethyl1-[(2'-{2-thienylsulfonylaminosulfonyl}biphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylate##STR176##

244 mg (0.5 mmol) of sulfonamide of Example 56e are dissolved in 10 mlof diethylene glycol dimethylether (anhydrous). 346 mg (2.5 mmol) of K₂CO₃ and 81 mg (0.5 mmol) of 2-thienyl sulfonyl chloride are then added.The reaction mixture is heated under reflux for 2 h, cooled and pouredinto 50 ml of 5% strength NaHSO₄ solution, and the mixture is extracted3 times with 50 ml of EA each time. The organic phase is dried overNa_(2SO) 4, concentrated on a rotary evaporator and chromatographedusing EA. 310 mg of pale yellow crystals, m.p.=120°-122° C., areobtained.

R_(f) (EA)=0.24 MS (FAB)=634 (M⁺ +H)

EXAMPLE 190

1-[(2'-{2-Thienylsulfonylaminosulfonyl}biphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylicacid ##STR177##

The hydrolysis of the ethyl ester from Example 189 is carried outanalogously to Example 56 f

R_(f) (EA/MeOH 5:1)=0.13 MS (FAB)=606 (M⁺ +H)

The compounds of the following Table 7 can be synthesized analogously toExample 189 or analogously to Example 190 (or 56f).

These compounds have the following formula F) ##STR178##

                  TABLE 7                                                         ______________________________________                                                 MS (FAB)                                                             Example  M.sup.+  + H  R        R'                                            ______________________________________                                        191      673           C.sub.2 H.sub.5                                                                        4-Nitrophenyl                                 192      645           H          "                                           193      579           H.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                               194      634           C.sub.2 H.sub.5                                                                        2-Thienyl                                     ______________________________________                                    

EXAMPLE 195

Ethyl1-[2'-methylaminocarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazole-5-carboxylate

In an autoclave, methylamine is introduced into 1 g of sulfonylcarbamatefrom Example 57 a in 50 ml of toluene at 80° C. for 5 min. The mixtureis then heated at 80° C. for 8 h. It is then concentrated in vacuo andthe residue is chromatographed on silica gel (EA/HEP 2:1), the titlecompound being obtained as an amorphous powder.

R_(f) (EA/HEP 2:1)=0.1 MS (FAB)=545 (M⁺ +H)

The compounds of the following Table 8 can be synthesized in ananalogous manner to that in Example 195 or 56f (the compound fromExample 195 is also listed).

These compounds have the formula C ##STR179##

                  TABLE 8                                                         ______________________________________                                              MS                                                                      Ex-   (FAB)                                                                   ample M.sup.+  + H                                                                           R       R'                                                     ______________________________________                                        195   545      --C.sub.2 H.sub.5                                                                     --CH.sub.3                                             196   517      H       --CH.sub.3                                             197   559      --C.sub.2 H.sub.5                                                                     --C.sub.2 H.sub.5                                      198   531      H       --C.sub.2 H.sub.5                                       199* 619      --C.sub.2 H.sub.5                                                                     --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2                                --OH                                                    200* 591      H       --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2         ______________________________________                                                               --OH                                                    *The compounds are synthesized analogously to Example 57.                

We claim:
 1. A compound of the formula (I) ##STR180## wherein thesymbols have the following meanings: R¹ is (C₂ -C₁₀)-alkyl, (C₃-C₁₀)-alkenyl, or (C₃ -C₈)-cycloalkyl;R⁵⁰ and R⁵¹ are each independentlyselected from --S(O)_(r) --R¹⁹, --CO--R⁸, and --O--R⁶ ; each R⁵ isindependently hydrogen or (C₁ -C₆)-alkyl; each R⁶ is independently(1)hydrogen; (2) (C₁ -C₆)-alkyl, which is optionally substituted by 1 to 3identical or different radicals selected from the group consisting of(C₁ -C₆)-alkoxy, hydroxy, carboxy, and (C₁ -C₄)-alkoxycarbonyl; (C₂-C₄)-alkenyl, which is optionally substituted by phenyl; or (C₃-C₆)-alkynyl;(3) (C₃ -C₈)-cycloalkyl, (C₃ -C₈)-cycloalkyl-(C₁-C₃)-alkyl; (4) (C₆ -C₁₂)-aryl; (5) (C₆ -C₁₀)-aryl-(C₁ -C₄)-alkyl, whichis optionally substituted by 1 or 2 identical or different radicalsselected from the group consisting of trifluoromethyl, methoxy, halogen,and --NR¹¹ R¹² ; (6) (C₁ -C₉)-heteroaryl, which is optionally partiallyor completely hydrogenated; (7) (C₂ -C₁₀)-alkenoyl; (8) (C₆ -C₁₂)-arylor (C₁ -C₉)-heteroaryl substituted by 1 or 2 identical or differentradicals selected from the group consisting of halogen, hydroxy,methoxy, nitro, cyano, trifluoromethyl, --NR¹¹ R¹² ; or (9) (C₁-C₉)-heteroaryl-(C₁ -C₃)-alkyl, where the heteroaryl moiety isoptionally partially or completely hydrogenated; each R⁸ isindependently hydrogen or --OR⁶ ; R⁹ is hydrogen, (C₁ -C₆)-alkyl, (C₃-C₈)-cycloalkyl or (C₂ -C₄)-alkenyl; R¹¹ and R¹² are, independently ofone another, hydrogen or (C₁ -C₄)-alkyl; A is a biphenyl radical whichis substituted by a radical R¹⁵ ; R¹⁵ is --SO₂ --NH--CO--NR⁶ R⁹, --SO₂--NH--COOR⁶, --SO₂ --NH--COR⁶, or --SO₂ --NH--SO₂ --NR⁶ R⁹ ; each R¹⁹ isindependently (C₁ -C₆)-alkyl, in which one to all of the hydrogen atomsis optionally substituted by fluorine; (C₃ -C₈)-cycloalkyl; phenyl; orbenzyl; r is zero, 1, or 2; and wherein (C₁ -C₉)-heteroaryl and (C₁-C₉)-heteroaryl- recited above are independently selected from the groupconsisting of furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyradazinyl, indolyl, indazolyl,quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, andcinnolinyl; or a physiologically tolerable salt thereof.
 2. A compoundof the formula (I) ##STR181## wherein the symbols have the followingmeanings: R¹ is (C₂ -C₁₀)-alkyl, (C₃ -C₁₀)-alkenyl, or (C₃-C₈)-cycloalkyl;R⁵⁰ and R⁵¹ are each independently selected from--S(O)_(r) --R¹⁹, --CO--R⁸, and --O--R⁶ ; each R⁵ is independentlyhydrogen or (C₁ -C₆)-alkyl; each R⁶ is independently(1) hydrogen; (2)(C₁ -C₆)-alkyl, which is optionally substituted by 1 to 3 identical ordifferent radicals selected from the group consisting of (C₁-C₆)-alkoxy, hydroxy, carboxy, and (C₁ -C₄)-alkoxycarbonyl;(C₂-C₄)-alkenyl; or (C₃ -C₆)-alkynyl; (3) (C₃ -C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁ -C₃ -alkyl; (4) (C₆ -C₁₂)-aryl; (5) (C₆-C₁₀)-aryl-(C₁ -C₄)-alkyl, which is optionally substituted by 1 or 2identical or different radicals selected from the group consisting oftrifluoromethyl, methoxy, halogen, and --NR¹¹ R¹² ; (6) (C₂-C₁₂)-alkenoyl; or (7) (C₆ -C₁₂)-aryl substituted by 1 or 2 identical ordifferent radicals selected from the group consisting of halogen,hydroxy, methoxy, nitro, cyano, trifluoromethyl, and --NR¹¹ R¹² ; eachR⁸ is independently hydrogen or --OR⁶ ; R⁹ is hydrogen, (C₁ -C₆)-alkyl,(C₃ -C₈)-cycloalkyl or (C₂ -C₄)-alkenyl; R¹¹ and R¹² are, independentlyof one another, hydrogen or (C₁ -C₄)-alkyl; A is a biphenyl radicalwhich is substituted by a radical R¹⁵ ; R¹⁵ is --SO₂ --NH--CO--NR⁶ R⁹,--SO₂ --NH--COOR⁶, --SO₂ --NH--COR⁶, or --SO₂ --NH--SO₂ --NR⁶ R⁶ ; eachR¹⁹ is independently (C₁ -C₆)-alkyl, in which one to all of the hydrogenatoms is optionally substituted by fluorine; (C₃ -C₈)-cycloalkyl;phenyl; or benzyl; r is zero, 1, or 2; or a physiologically tolerablesalt thereof.
 3. A compound of claim 1 or a physiologically tolerablesalt thereof, wherein:R is (C₂ -C₁₀)-alkyl; each R⁵⁰ and R⁵¹ isindependently --SCH₃ or --CO--R⁸ ; each R⁶ is independently hydrogen or(C₁ -C₆)-alkyl; each R⁸ is independently hydrogen or --OR⁶ ; R⁹ ishydrogen, (C₁ -C₆)-alkyl, or (C₂ -C₄)-alkenyl; A is a biphenyl radicalwhich is substituted by a radical R¹⁵ ; and R¹⁵ is --SO₂ --NH--CO--NR⁶R⁹.
 4. A pharmaceutical composition comprising an effective amount ofthe compound of claim 1 or a physiologically tolerable salt thereof anda pharmaceutically utilizable excipient.
 5. A pharmaceutical compositioncomprising an effective amount of the compound of claim 2 or aphysiologically tolerable salt thereof and a pharmaceutically utilizableexcipient.
 6. A pharmaceutical composition comprising an effectiveamount of the compound of claim 3 or a physiologically tolerable saltthereof and a pharmaceutically utilizable excipient.
 7. A method for thetreatment of high blood pressure which comprises administering to asubject in recognized need of treatment for high blood pressure aneffective amount of the compound of claim 1 or a physiologicallytolerable salt thereof.
 8. A method for the treatment of high bloodpressure which comprises administering to a subject in recognized needof treatment for high blood pressure an effective amount of the compoundof claim 2 or a physiologically tolerable salt thereof.
 9. A method forthe treatment of high blood pressure which comprises administering to asubject in recognized need of treatment for high blood pressure aneffective amount of the compound of claim 3 or a physiologicallytolerable salt thereof.
 10. A compound of claim 1, wherein the compoundis ethyl1-[(2'-n-propyl-aminocarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazol-5-carboxylateor a physiologically tolerable salt thereof.
 11. A compound of claim 1,wherein the compound is1-[(2-'-n-propyl-aminocarbonylaminosulfonylbiphenyl-4-yl)methyl]-2-n-butyl-4-methylthioimidazol-5-carboxylicacid or a physiologically tolerable salt thereof.
 12. A pharmaceuticalcomposition comprising an effective amount of the compound of claim 11or a physiologically tolerable salt thereof and a pharmaceuticallyutilizable excipient.
 13. A pharmaceutical composition comprising aneffective amount of the compound of claim 10 or a physiologicallytolerable salt thereof and a pharmaceutically utilizable excipient. 14.A method for the treatment of high blood pressure which comprisesadministering to a subject an effective amount of the compound of claim11 or a physiologically tolerable salt thereof.
 15. A method for thetreatment of high blood pressure which comprises administering to asubject an effective amount of the compound of claim 10 or aphysiologically tolerable salt thereof.
 16. A compound of claim 1 or aphysiologically tolerable salt thereof, wherein R⁵⁰ is --S(O)_(r) --R¹⁹or --O----R⁶ and R⁵¹ is --CO--R⁸.
 17. A compound of claim 1 or aphysiologically tolerable salt thereof, wherein R⁵⁰ is --S(O)_(r) --R¹⁹and R⁵¹ is --CO--R⁸.